Working from the assumption that fragment condensation schemes for peptide synthesis can be made vastly more practical through development of new synthetic reagents, we are seeking new coupling agents and protective groups which can improve the convenience of synthetic operations and maximize purity of products. Our method has two unusual features: we plan to draw upon the implications of detailed studies of peptide mechanisms fo the design of synthetic reagents, and we propose to develop reagents which are tailored to meet the differing needs of protection and coupling as the problems are encountered at the beginning, the middle, and at the end of a fragment synthesis. Provided we are successful in these aims, the long range objectives of this study become the synthesis of the biologically important large peptides, ranging on the one hand to the enzymes of known structure, for which synthesis may well prove to be the final and most incisive tool for determining catalytic mechanism, and on the other hand, to the hormones, particularly those which have important medicinal uses and which cannot be replaced by animal-derived biologicals. Examples include human insulin, human growth hormone, and perhaps, when purification and sequence-assignment has been carried out, portions of antibodies and interferon.